Clinical and Economic Value of Anti-Xa Monitoring in ...education.healthtrustpg.com/wp-content/uploads/2016/02/Anti-Xa-Presentation.pdfOur Passion. Your Results. Monitoring UF Heparin

Clinical and Economic Value of

Anti-Xa Monitoring in Patients

Receiving Unfractionated

Heparin

Kathy Shingler, MT (ASCP)

Clinical Hemostasis

Our Passion. Your Results.

Disclosure

• Financial relationship of presenter: Employed by

Instrumentation Laboratory

• The study presented in this presentation has been funded

by Instrumentation Laboratory and has been accepted for

publication. The retrospective cohort study assay methods

were not restricted to a specific vendor.


Affordable Care Act: Triple Aim


Objectives

• Describe the role of heparin as an anticoagulant

• Explain why monitoring unfractionated heparin (UFH) with

Anti-Xa is superior to aPTT

• Review results of a study comparing Anti-Xa monitoring

with aPTT in patients on UFH therapy

• Outline a plan to ensure a smooth transition from aPTT to

Anti-Xa monitoring


What is Heparin?

• Widely used anticoagulant

discovered in 1916

• Used for treatment and

prevention of thrombotic

diseases

• Maintains blood fluidity in

extracorporeal devices

• Chains of sulfated

glycosaminoglycans

• Molecular weight: 5,000 –

30,000 daltons

Heparin Molecule

http://circ.ahajournals.org


Clinical Use of Unfractionated Heparin

• Antithrombotic agent – high dose • Acute thrombosis

• Prophylaxis – low dose to prevent thrombosis • Pre/post-surgery: orthopedic, general, vascular

• Prevention of VTE and preeclampsia recurrence during

pregnancy

• Acutely ill patients: congestive heart failure, severe

respiratory disease

• Maintenance of arterial and venous lines • Possible heparin contamination

• Potentially high-risk

• “Drug widely used…that has a high risk of patient injury when

administered incorrectly.”

Niccolai CS, et al. Unfractionated heparin: focus on a high-alert drug. Pharmacotherapy

2004;24:146S-155S.


Clotting Enzyme Inactivation by Heparin

AT Clotting

Enzyme

Chest 2012; E25S

AT is a slow Inhibitor without heparin



AT Clotting

Enzyme

AT Clotting

Enzyme

Heparin

Chest 2008;133: 141-159

AT is a slow Inhibitor without heparin

• Heparin binds to AT through a high-affinity pentasaccharide

• Conformational change to AT converts AT from slow to rapid

inhibitor (2-3X)



AT Clotting

Enzyme AT is a slow Inhibitor without heparin

AT Clotting

Enzyme

Heparin

AT Clotting

Enzyme

Heparin

• AT binds covalently to clotting enzyme

• Heparin dissociates itself from the complex and can be

reutilized

Chest 2008;133: 141-159

• Heparin binds to AT through a high affinity pentasaccharide

• Conformational change to AT converts AT from slow to very

rapid inhibitor (2-3X)


FXI

FIX

FXII

FX

FVII

FII Thrombin

Fibrinogen Fibrin

FVIII

FV

Coagulation Cascade: in vitro Model

HEPARIN A non-specific inhibitor

aPTT PT


UFH-Binding Candidates

ACCP 2012 9th Edition/CHEST Supplement 2012; chestjournal.chestpubs.org, e28S, e29S


Monitoring UF Heparin

• For venous thrombosis - Heparin Anti-Xa: 0.3 – 0.7 Anti-Xa units

- aPTT

• Correlated to 0.3 – 0.7 Anti-Xa units

• 0.2 – 0.4 units by protamine sulfate titration

• For coronary indications - The therapeutic range is unknown but is likely to correspond to

heparin levels approximately 10% lower than used to treat patients

with VTE

• Monitoring required - Variable dose-response rate, due to binding to proteins

- Varying rates of heparin clearance

- Ensures patient is not sub-therapeutic or over anti-coagulated

ACCP 2012 9th Edition/CHEST Supplement 2012; chestjournal.chestpubs.org, e28S, e29S


Heparin Monitoring with aPTT

• aPTT - traditional method (1.5 - 2.5x “control”) - Based on a retrospective study (1970s)

- Not confirmed with randomized clinical trials

• In vitro heparin dose-response curve - Spiked normal plasma with UFH

- Not recommended by CAP, over-estimates when compared with

patient samples

• Ex vivo heparin therapeutic range using aPTT and Anti-Xa

assay - Recommended method by CAP

ACCP 2012 9th Edition/CHEST Supplement 2012; chestjournal.chestpubs.org, e28S


Drawbacks to aPTT

• Does not directly measure heparin

• Variable responsiveness of aPTT reagents

• aPTT cannot be used to monitor LMWH, fondaparinux,

rivaroxaban, apixaban, edoxaban

• High base-line aPTT (Lupus Anticoagulant, Factor

deficiency)

• Increased Factor VIII, Fibrinogen


• aPTT response to anticoagulant therapy is exaggerated

• Numerous factors may elevate aPTT - Concomitant warfarin therapy

- Lupus anticoagulant

- Factor deficiency

- Liver disease

Monitoring Anticoagulant Therapy

Using the aPTT


Monitoring with aPTT Increases in Acute Phase Reactants

• Under-estimates anticoagulation level

• Factor VIII and Fibrinogen increases - Can shorten the aPTT in a clinically significant manner

- Factor VIII increases from 100 - 600% can shorten aPTT by 33-50%

• One cause of in vitro drug “resistance”

Effects of factor VIII levels on the APTT and anti-Xa activity under a therapeutic dose of heparin.Int J Hematol. 2015 Feb ;101(2):119-25. doi: 10.1007/s12185-014-1702-z. Epub 2014 Nov 23


Heparin Anti-Xa to aPTT Correlation (Treatment Dosing)

0

20

40

60

80

100

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5

Anti-Xa u/ml

aP

TT

se

cs

Y

aPTT vs Anti-Xa in Pregnant Population

Adcock DM; Tillman D. unpublished 1998

Unpublished study courtesy of Dr. D Adcock


Establishing the Therapeutic Range for aPTT

with Anti-Xa

• Preferred method (e.g., ISTH, CAP)

• Collect samples from patients receiving heparin only - Normal PT - Minimum 50 - No more than two samples from the same patient

• Perform aPTT and Anti-Xa testing - Can freeze samples for Anti-Xa testing later - follow CLSI guidelines - If samples are frozen, repeat aPTT after thawing for quality check

• Plot heparin vs aPTT using regression analysis

• Determine the aPTT therapeutic range corresponding to 0.3 - 0.7 U/mL


55

85

Anti-Xa Therapeutic Range

Sub-therapeutic

Therapeutic

Supra-therapeutic

Data obtained from a typical hospital laboratory

Therapeutic Heparin Range


Evaluation of Outcomes in Anti-Xa

Vs aPTT Monitored Patients

Receiving Unfractionated Heparin


Anti-Xa vs APTT Publications

Outcome Price, Ann

Pharmacother 2013

Guervil, Ann

Pharmacother

2011

Vandiver, Pharmacother

2012

Smith, Am J

Health-Syst

Pharm 2010

Rosborough,

Pharmacother 1999

Length of Stay X

Faster Time to

Therapeutic X X

Discordant Results X

Fewer Dosage

Changes/Tests X X X

Cost per Test Xa $13.30 vs

PTT $13.97

Xa $31.46 vs

PTT $27.10

Adverse Outcomes X

Economic

Outcomes N/A N/A N/A N/A N/A

Number of Sites 1 1 1 1 1


Key Points of the IL Study

• Scope

- Compare performance of Anti-Xa vs aPTT assays for patients on UFH treatment

• Outcomes with Anti-Xa

- Significant hospital cost savings in patient care

- Significant reduction in patient complications (e.g., major hemorrhage, VTE, mortality)

• Disease state

- Focus on VTE, Acute Coronary Syndrome, Stroke and complications (e.g., hemorrhage, thrombosis)

• Method - Data Analytics Group retrospective review of key markers

in large multi-hospital database

22

Slides 21 – 57: Belk KW, Laposata M, Craver CW, Comparison of bleeding complications between Anti-Xa and aPTT monitoring in patients Receiving unfractionated heparin, International Society on Thrombosis and

Hemostasis 13 (Suppl 2) 213, 2015.


Database Contents

• Hospital characteristics - region, bed size, teaching status

• Patient demographics - Age, gender

• Diagnosis - ICD-9 diagnosis codes, clinical groupings (MS-DRG)

• Procedure - ICD-9 procedure codes, CPT codes, procedure date

• Metrics - Length of stay, mortality, readmissions


Anti-Xa Study Design

• Create a patient-matching algorithm to identify “like”

patients in aPTT and Anti-Xa cohorts

• Matching variables for all populations included: - Hospital bed size and teaching status

- Hospital region

- Patient age

- Gender

- Patient comorbidities

- Transfers to another facility and left against medical advice


Study Population

Patients on IV UFH discharged over 5 years

(2009-2013)

Monitored with aPTT

Venous Thromboembolism

as primary diagnosis (VTE)

Stroke Acute Coronary Syndrome (ACS)

Monitored with Anti-Xa

Venous Thromboembolism

as primary diagnosis (VTE)

Stroke Acute Coronary Syndrome (ACS)

The two cohorts were defined using CPT codes and the name of the assay. Matched cohorts included: • N= 2207 for Venous Thromboembolism (VTE) • N= 784 for Stroke • N= 7411 for Acute Coronary Syndrome (ACS)


Study Design - Outcomes Included

Overall cost of care Length of stay Number of

monitoring tests

Number of heparin dose changes

Readmissions In-hospital mortality

Complications:

- RBC transfusions

- Protamine Sulfate

- Thromboses


Statistical Methods Used

• Univariate: Observing only one variable at a time - Numeric data

• Variance (how widely point varies from the mean)

- Qualitative data

• Chi-square (compares the significant difference of two variables)

• Multi-variate analysis: Observing multiple variables to

isolate the impact of Anti-Xa on outcomes - Regression (compares points to show cause and effect)

• p value < 0.05 is considered significant


Venous Thromboembolism (VTE)

Results


VTE: Cost of Care

Median cost of care for

patients monitored with

Anti-Xa was $808 less

than those monitored

with aPTT 7,923

8,730

7000

7500

8000

8500

9000

Anti-Xa aPTT

Median Cost

(N = 2207, p = 0.0022)

$


VTE: Number of Heparin Dose Changes

Average number of

heparin dose

changes was lower

in patients

monitored with

Anti-Xa

1.48 1.61

0.00

0.50

1.00

1.50

2.00

Anti-Xa aPTT

Mean Number of Heparin Dose Changes

(N = 2207, p = 0.0365)


VTE: Number of Monitoring Tests Administered

On average, patients

monitored with Anti-Xa

had two fewer tests than


aPTT.

• For a larger hospital with

75-150 VTE patients on

unfractionated heparin

annually, this results in a

difference of 150-300 tests.

5.53

7.51

0.00

2.00

4.00

6.00

8.00

Anti-Xa aPTT

Mean Number of Tests Administered

(N = 2207, p <0.0001)


VTE: RBC Blood Transfusions

Patients monitored with Anti-Xa had nearly 5% fewer RBC blood transfusions

• Average cost of care for patients with a transfusion is twice as much as those without transfusions ($29,943 vs. $11,248)

3.90

8.61

0%

2%

4%

6%

8%

10%

Anti-Xa aPTT

RBC Blood Transfusions

(N = 2207, p < 0.0001)


VTE: In-Hospital Mortality

There were no

significant

differences for in-

hospital mortality for


Anti-Xa compared to

those monitored with

aPTT.

2.36 2.40

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

Anti-Xa aPTT

In-Hospital Mortality

(N = 2207, p = 0.9213)


VTE: Multivariate Results

• Evaluation of the cost, length of stay, readmission and

mortality measures using multi-variate regression showed

estimated savings of $402 for patients with Anti-Xa

For a large hospital with 75-150 VTE patients on UFH, this saves

$30,000-$60,000 annually


VTE: Multi-variate Blood Complication Results

• Patients tested with aPTT were 2.8 times more likely to get

a RBC transfusion than those patients tested with Anti-Xa

• Controlled for - Patient age and gender

- Diagnostic risks

- Invasive procedures

The average cost of treating

patients with a transfusion was

2x as those without

transfusions ($29,943 vs.

11,248)


Stroke Results


Stroke: Cost of Care

The median cost of

care for patients tested

with Anti-Xa was

$3,454 less than those

who were using the

aPTT; however, this

result is not statistically

significant.

17,387

20,841

15,000

16,000

17,000

18,000

19,000

20,000

21,000

22,000

Anti-Xa aPTT

Median Cost

(N = 784, p = 0.1526)

$


Stroke: Number of Heparin Dose Changes

The average number

of heparin dose

changes was lower

in patients tested

with Anti-Xa.

1.67

1.96

0.00

0.50

1.00

1.50

2.00

2.50

Anti-Xa aPTT


(N = 784, p = 0.0276)


Stroke: Number of Monitoring Tests

Administered



had approximately one

more test than those

monitored with aPTT.

6.76

5.61

0

2

4

6

8

Anti-Xa aPTT


(N = 784, p = 0.0104)


Stroke: Blood Transfusions

Patients monitored with

Anti-Xa had

approximately an 8%

reduction in RBC

transfusions.

• Average cost of care for

patients with transfusion

is >3X those without

($88,630 vs. $25,575)

13.78

21.94

0%

5%

10%

15%

20%

25%

Anti-Xa aPTT


N = 784, p < 0.0001


Stroke: In-Hospital Mortality

No significant

difference in-hospital

mortality for patients


vs. aPTT

9.44 10.08

0%

2%

4%

6%

8%

10%

12%

Anti-Xa aPTT


N = 784, p = 0.6705


Stroke Multivariate Results

• Evaluation of the cost, length of stay, readmission and

mortality measures using multi-variate regression

demonstrated: - Estimated savings of $1,932 for patients with Anti-Xa

• For a large hospital with 200-350 stroke patients treated with UFH, this would result in estimated $350,000 - $700,000

savings annually*

• No significant differences in length of stay, readmissions or mortality

*Hall MJ, Levant S, DeFrances C, “Hospitalization for Stroke in U.S. Hospitals 1989-2009”, NCHS Data Brief, No. 95, May 2012


Stroke: Multivariate Blood Complication Results

• Patients monitored with aPTT were 2.5 times more likely

to receive an RBC transfusion than those on Anti-Xa

• Study was controlled for: - Patient age and gender

- Diagnostic risks

• (e.g., anemia, renal insufficiency, trauma)


• (e.g., cardiac catheterization, hemodialysis, coronary artery bypass graft)

.


Acute Coronary Syndrome (ACS)

Results


ACS: Cost of Care

Median cost of care

for patients monitored

with Anti-Xa was

$3,982 less than


aPTT 17,162

21,144

15,000

16,000

17,000

18,000

19,000

20,000

21,000

22,000

Anti-Xa aPTT

Median Cost

(N = 7411, p < 0.0001)

$


ACS: Length of Stay

Average length of stay

for patients monitored

with Anti-Xa was more

than half a day less

than those monitored

with aPTT

7.94 8.60

0.00

2.00

4.00

6.00

8.00

10.00

Anti-Xa aPTT

Mean Length of Stay

N = 7411, p <0.0001


ACS: Number of Heparin Dose Changes

Average number of

heparin dose changes

was higher in patients


1.80

1.44

0.00

0.50

1.00

1.50

2.00

Anti-Xa aPTT


(N = 7411, p < 0.0001)


ACS: Number of Monitoring Tests Administered



had 0.44 fewer tests than


aPTT.

• For a larger hospital

with 500-900 ACS

patients on

unfractionated heparin

annually, this would

translate to a difference

of 200-400 tests

annually.

3.80 4.24

0

1

2

3

4

5

Anti-Xa aPTT


N = 7411, p < 0.0001

Te

sts


ACS: RBC Blood Transfusions

Patients monitored with

Anti-Xa had nearly 18%

fewer RBC blood

transfusions.

• Average cost of

patients with a

transfusion was 2x

that of those without

transfusions ($51,650

vs. $22,373)

7.02

24.56

0%

5%

10%

15%

20%

25%

30%

Anti-Xa aPTT


(N = 7411, p < 0.0001)


ACS: In-Hospital Mortality

Mortality rate in


Anti-Xa was nearly 1%

less than that in


aPTT

9.44% 10.08%

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

Anti-Xa aPTT


(N = 7411, p = 0.0275)


ACS Multi-variate Results

Evaluation of the cost, length of stay, readmission and

mortality measures using multi-variate regression

demonstrated:

• Estimated savings of $741 for patients monitored with

Anti-Xa - For a large hospital with 500-900 ACS patients on UFH, annual

mean savings estimated to be $350,000 - 700,000

• Estimated savings of 9.9 hospital hours for patients

monitored with Anti-Xa - For a large hospital with 500-900 ACS patients treated with UFH,

estimated 200-375 days annually


ACS: Multivariate Blood Complication Results

• Patients monitored with aPTT were 6.3 times more likely

to receive a RBC transfusion and 1.7 times more likely to

receive protamine sulfate than patients monitored with

Anti-Xa.

• Controlled for: - Patient age and gender

- Diagnostic risks

• (e.g., anemia, renal insufficiency, trauma)


• (e.g., cardiac catheterization, hemodialysis, coronary artery bypass graft)


VTE: Summary of the Advantages of Anti-Xa

Anti-Xa

aPTT

$808 reduction in cost of care pp

Fewer RBC transfusions

2 less tests per

VTE patient

Fewer dose

changes

Note: Length of stay, mortality, readmission, thrombotic complication rate, and

protamine titration incidence were not significantly different


Stroke: Summary of the Advantages of Anti-Xa

Anti-Xa aPTT

$3,454 lower cost of care pp

fewer RBC transfusions

Fewer dose

changes

Note: Length of stay, mortality, thrombotic complications, readmission rate and

protamine titration incidence were not significantly different

Fewer monitoring

tests


ACS: Summary of the Advantages of Anti-Xa

Anti-Xa

aPTT

$3,982 lower cost of care

18% fewer RBC

transfusions

Fewer tests ACS

patients

Fewer dose

changes

Note: Re-admission and thrombotic complication rate were not significantly

different

9.9 hour reduction in hospital

stay

Mortality decreased

1%


Multi-variate Results

• Examination of the cost, length of stay, readmission and mortality measures using multi-variate regression demonstrated:

- Estimated savings of

• $402 for VTE patients with Anti-Xa • For a large hospital with 75–150 VTE patients treated with UFH, this saves

$30,000–$60,000 annually

- $1,932 for Stroke patients with Anti-Xa • For a large hospital with 200-350 Stroke patients on UFH, this saves $350,000–

$700,000 annually

- $741 for ACS patients with Anti-Xa • For a large hospital with 500-900 ACS patients on UFH, this saves $350,000–

$700,000 annually

- 9.9 hours ACS for patients with Anti-Xa • For a large hospital with 500-900 ACS patients on UFH, this saves estimated

200–375 hospital days annually


VTE Stroke ACS

Patients/

Year

75 – 250 200 – 350 500 - 900

Cost savings/

Patient ($)

402 1932 741

Savings/

year ($)

30,150 – 60,300 386,400 – 676,200 370,500 – 666,900

Estimate of Financial Benefit – Large U.S.

Hospital

57

TOTAL Annual Savings = $790,000 – $1,400,000


Hypothesis to Explain Link Between Decline in

RBC Transfusions and Anti-Xa Monitoring

• Anti-Xa assay use focuses more attention on the use of blood

products, which causes a reduction in use

• Monitoring Heparin therapy with Anti-Xa assay involves more

specialists in coagulation and transfusion medicine, resulting in

more careful, evidenced-based transfusion decisions

• The use of the Anti-Xa assay provides a more accurate

assessment of anticoagulant-associated bleeding risk and, thus,

reduces the need for RBC transfusions

Dr. Michael Laposata, AACC

Hemostasis workshop July 2015


Successful Implementation of the

Anti-Xa Assay


Educate and Convince

• Present to pharmacy department to demonstrate value - Lab leadership: meet with pharmacy leadership and present

data/references demonstrating the benefit of the Anti-Xa assay

• Present the change to caregivers - Lab and Pharmacy jointly present to Nursing and Physician

leadership

- Present the benefits of the change

• Improved patient care

• Cost benefit

• More precise measurement of heparin concentration


Add to Electronic Medical Record

• Set up new orderable Anti-Xa assay(s) - Include therapeutic ranges for both UFH and LMWH

• UFH = 0.3 – 0.7 IU/mL

• LMWH = varies by type

• List the range for the most commonly used drugs

• Set up new heparin protocol(s) based on Anti-Xa

monitoring - For VTE (DVT and PE)

- For ACS/Stroke – patients with an increased risk of bleeding


Heparin Dosing for VTE

Anti-Xa

(IU/mL)

Bolus Dose

(units/kg)

Stop Infusion

(min)

Rate Change

(Units/kg/h)

Initial dose 80 18 (initial rate)

<0.2 80 Increase by 4

0.2-0.29 40 Increase by 2

0.3-.07 No No change

0.71-0.8 No Decrease by 1

0.81-0.9 No 30 Decrease by 2

>0.9 No 60 Decrease by 3

Ann Pharmacother 2011;45;861-8


Low Intensity Heparin Dosing for ACS and

Stroke

Used with permission from Univ of NM MC Pharmacy


Caregiver Training on New Heparin Protocols

• Nursing continuing

education/competency

program - Available as online

presentation or live

- Educates on why the change to

Anti-Xa and the benefits

• Physician training - Grand Rounds

- Department meetings


Who to Target:

Pharmacy & Therapeutics Committees

• Pharmacy Newsletter Article - Briefly describe reason behind the change


Notification of the Change

• Laboratory bulletins - Include other hospitals using

Anti-Xa (local if possible)

- Describe assay and its benefits

vs. the APTT

- Include new therapeutic range

- State what is changing (i.e.

dosing nomogram) and what is

not

- Mention that pharmacy is in

agreement/involved

Letter courtesy of Dr. Higgins, UHS San Antonio, TX


Challenges to Acceptance

• Need to move beyond a departmental budget and to a

focus on improving patient care - Reagent costs will increase for the lab

- Overall cost to the medical center will be reduced

- Nursing department must have adequate time for complete training

before “going live” with Anti-Xa


• Monitoring UFH therapy with the Anti-Xa assay can help

achieve the “Triple Aim” for healthcare improvement

- Patient care will improve by maintaining levels of

anticoagulation and reducing RBC transfusions

- Patient experience will improve with fewer tests and fewer

dose changes

- Cost of hospital care is reduced

Conclusions

68

4/7/2016

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Clinical and Economic Value of Anti-Xa Monitoring in ...education.healthtrustpg.com/wp-content/uploads/2016/02/Anti-Xa-Presentation.pdfOur Passion. Your Results. Monitoring UF Heparin